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Population Pharmacokinetics of Daclizumab High-Yield Process in Healthy Volunteers: Integrated Analysis of Intravenous and Subcutaneous, Single- and Multiple-Dose Administration

Abstract

Background and Objective

Daclizumab is a humanized monoclonal antibody that blocks the α-subunit of the interleukin-2 receptor with demonstrated benefits in the treatment of multiple sclerosis. The present work aimed to characterize the pharmacokinetics of daclizumab high-yield process (HYP) in healthy volunteers.

Methods

Three double-blind, randomized, placebo-controlled, phase I studies evaluated the pharmacokinetics of daclizumab HYP in healthy volunteers following single subcutaneous administration (50, 150, or 300 mg), multiple subcutaneous administrations (100 or 200 mg biweekly with a 200 mg loading dose), or single intravenous administration (200 or 400 mg). Measurable serum concentrations (n = 925) from 70 subjects treated with daclizumab HYP in the three studies were analyzed using non-linear mixed-effects modeling.

Results

A two-compartment model with a first-order absorption and elimination adequately described daclizumab HYP pharmacokinetics. Daclizumab HYP clearance, inter-compartmental clearance, and central and peripheral volumes of distribution were 10 mL/h, 44 mL/h, 3.89 L, and 2.52 L, respectively, scaled by [bodyweight (kg)/70] with 0.54 and 0.64 exponents for clearance and volume parameters, respectively. Lag-time, mean absorption time, and absolute bioavailability (100–300 mg) for subcutaneous administration were 2 h, 4.6 days, and 84 %, respectively. Bodyweight explained only ~20 % of daclizumab HYP pharmacokinetic variability. With this limited dataset, sex, age, race, or presence of antibodies did not correlate with daclizumab HYP clearance. The estimated effective half-life was 21–25 days. The developed model was robust in bootstrap evaluation and predicted the data adequately in stochastic simulations.

Conclusions

Daclizumab HYP is characterized by slow clearance, linear pharmacokinetics (at doses ≥100 mg), high subcutaneous bioavailability, and a half-life suitable for monthly administration.

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Competing interest

AbbVie contributed to the study design, research, and interpretation of data, writing, reviewing, and approving the publication. Drs. Othman and Dutta are employees and shareholders of AbbVie. Dr. Tang is a previous employee of Facet Biotech (which was acquired by AbbVie) and is currently an employee of Genentech and a shareholder of Roche. Dr. Tran is an employee and a shareholder of Biogen Idec. Dr. Othman conducted the population pharmacokinetic analysis and all authors contributed to interpretation of the data, writing, reviewing, and approving the manuscript. Daclizumab HYP is currently under development by AbbVie and Biogen Idec for treatment of multiple sclerosis. The authors declare no other relationships or activities that could appear to have influenced the submitted work.

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Correspondence to Ahmed A. Othman.

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Othman, A.A., Tran, J.Q., Tang, M.T. et al. Population Pharmacokinetics of Daclizumab High-Yield Process in Healthy Volunteers: Integrated Analysis of Intravenous and Subcutaneous, Single- and Multiple-Dose Administration. Clin Pharmacokinet 53, 907–918 (2014). https://doi.org/10.1007/s40262-014-0159-9

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  • DOI: https://doi.org/10.1007/s40262-014-0159-9

Keywords

  • Multiple Sclerosis
  • Multiple Sclerosis Patient
  • Subcutaneous Administration
  • Daclizumab
  • Visual Predictive Check